This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥ 1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA.

KEYTRUDA as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy (see section 5.1).

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with a combined positive score (CPS) ≥ 10 (see section 5.1).

KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy (see section 5.1).

4.2 Posology and method of administration

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer.

PD-L1 testing for patients with NSCLC, urothelial carcinoma, or HNSCC

Testing for PD-L1 tumour expression using a validated test is recommended for patients with NSCLC. In patients with NSCLC whose tumours have high PD-L1 expression, the risk of adverse reactions with combination therapy relative to pembrolizumab monotherapy should be considered and the benefit/risk ratio of the combined therapy evaluated on an individual basis (see sections 4.1, 4.4, 4.8 and 5.1).

Patients with previously untreated urothelial carcinoma or HNSCC should be selected for treatment based on the tumour expression of PD-L1 confirmed by a validated test (see section 5.1).

Posology

The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks.

Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity. Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year.

For patients with Grade 3 or Grade 4 endocrinopathy that improved to Grade 2 or lower and is controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued.

Hypothyroidism may be managed with replacement therapy without treatment interruption.

Hepatitis

Grade 2 with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 to 5 times ULN or total bilirubin > 1.5 to 3 times ULN

Withhold until adverse reactions recover to Grade 0-1*

Grade ≥ 3 with AST or ALT > 5 times ULN or total bilirubin > 3 times ULN

Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4).

* If treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of KEYTRUDA, or if corticosteroid dosing cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks, KEYTRUDA should be permanently discontinued.

The safety of re-initiating pembrolizumab therapy in patients previously experiencing immune-related myocarditis is not known.

For Grade 4 haematological toxicity, only in patients with cHL, KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1.

Patients treated with KEYTRUDA must be given the Patient Alert Card and be informed about the risks of KEYTRUDA (see also package leaflet).

Special populations

Elderly

No dose adjustment is necessary in patients ≥ 65 years (see section 5.1). Data from patients ≥ 65 years are too limited to draw conclusions on cHL population (see section 5.1). Data from pembrolizumab monotherapy in patients with resected Stage III melanoma and from chemotherapy combination in patients with metastatic NSCLC ≥ 75 years are limited (see sections 4.4 and 5.1).

Renal impairment

No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has not been studied in patients with severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is needed for patients with mild hepatic impairment. KEYTRUDA has not been studied in patients with moderate or severe hepatic impairment (see sections 4.4 and 5.2).

Ocular melanoma

There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma (see section 5.1).

The safety and efficacy of KEYTRUDA in children below 18 years of age have not yet been established. No data are available.

Method of administration

KEYTRUDA must be administered by intravenous infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection.

When administering KEYTRUDA as part of a combination with chemotherapy, KEYTRUDA should be administered first. See also the prescribing information for the chemotherapy agents administered in combination.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Assessment of PD-L1 status

When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations.

Immune-related adverse reactions

Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously.

For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or exclude other causes should be ensured. Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid taper should be initiated and continued over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse reaction remains at Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day.

Pembrolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction that recurs and for any Grade 4 immune-related adverse reaction toxicity, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).

Immune-related pneumonitis

Pneumonitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); pembrolizumab should be withheld for Grade 2 pneumonitis, and permanently discontinued for Grade 3, Grade 4 or recurrent Grade 2 pneumonitis (see section 4.2).

Immune-related colitis

Colitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of colitis, and other causes excluded. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); pembrolizumab should be withheld for Grade 2 or Grade 3 colitis, and permanently discontinued for Grade 4 colitis (see section 4.2). The potential risk of gastrointestinal perforation should be taken into consideration.

Immune-related hepatitis

Hepatitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded. Corticosteroids should be administered (initial dose of 0.5-1 mg/kg/day (for Grade 2 events) and 1-2 mg/kg/day (for Grade ≥ 3 events) prednisone or equivalent followed by a taper) and, based on severity of liver enzyme elevations, pembrolizumab should be withheld or discontinued (see section 4.2).

Immune-related nephritis

Nephritis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for changes in renal function, and other causes of renal dysfunction excluded. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper) and, based on severity of creatinine elevations, pembrolizumab should be withheld for Grade 2, and permanently discontinued for Grade 3 or Grade 4 nephritis (see section 4.2).

Long-term hormone replacement therapy may be necessary in cases of immune-related endocrinopathies.

Hypophysitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and other causes excluded. Corticosteroids to treat secondary adrenal insufficiency and other hormone replacement should be administered as clinically indicated, and pembrolizumab should be withheld for symptomatic hypophysitis until the event is controlled with hormone replacement. Continuation of pembrolizumab may be considered, after corticosteroid taper, if needed (see section 4.2). Pituitary function and hormone levels should be monitored to ensure appropriate hormone replacement.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Insulin should be administered for type 1 diabetes, and pembrolizumab should be withheld in cases of Grade 3 hyperglycaemia until metabolic control is achieved (see section 4.2).

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism is more frequently reported in patients with HNSCC with prior radiation therapy. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab should be withheld for Grade ≥ 3 until recovery to Grade ≤ 1 hyperthyroidism. For patients with Grade 3 or Grade 4 hyperthyroidism that improved to Grade 2 or lower, continuation of pembrolizumab may be considered, after corticosteroid taper, if needed (see sections 4.2 and 4.8). Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.

Immune-related skin adverse reactions

Immune-related severe skin reactions have been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued, and corticosteroids should be administered (see section 4.2).

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving pembrolizumab (see section 4.8). For signs or symptoms of SJS or TEN, pembrolizumab should be withheld and the patient should be referred to a specialised unit for assessment and treatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued (see section 4.2).

Caution should be used when considering the use of pembrolizumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune- stimulatory anticancer agents.

Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroids administered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse reaction remains at Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day.

Pembrolizumab must be permanently discontinued for any Grade 3 immune related adverse reaction that recurs and for any Grade 4 immune related adverse reaction (see sections 4.2 and 4.8).

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with pembrolizumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients.

Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case (see section 4.8).

Allogeneic HSCT prior to treatment with pembrolizumab

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

Infusion-related reactions

Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported in patients receiving pembrolizumab (see section 4.8). For severe infusion reactions, infusion should be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with mild or moderate infusion reaction may continue to receive pembrolizumab with close monitoring; premedication with antipyretic and antihistamine may be considered.

Disease-specific precautions

Use of pembrolizumab in urothelial carcinoma patients who have received priorplatinum-containing chemotherapy

Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In urothelial cancer, a higher number of deaths within 2 months was observed in pembrolizumab compared to chemotherapy (see section 5.1). Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.

Use of pembrolizumab in urothelial cancer for patients who are considered ineligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS ≥ 10

The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 included a proportion of patients eligible for a carboplatin-based combination, for whom the benefit is being assessed in a comparative study, and patients eligible for mono-chemotherapy, for whom no randomised data are available. In addition, no safety and efficacy data are available in frailer patients (e.g., ECOG performance status 3) considered not eligible for chemotherapy. In the absence of these data, pembrolizumab should be used with caution in this population after careful consideration of the potential risk-benefit on an individual basis.

Use of pembrolizumab for first-line treatment of patients with NSCLC

In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed to be higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions of each of these components (see sections 4.2 and 4.8). A direct comparison of pembrolizumab when used in combination with chemotherapy to pembrolizumab monotherapy is not available.

Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in previously untreated patients with non-small cell lung cancer whose tumours express PD-L1.

Efficacy and safety data from patients ≥ 75 years are limited. For patients ≥ 75 years, pembrolizumab combination therapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis (see section 5.1).

Use of pembrolizumab for adjuvant treatment of patients with melanoma

A trend toward increased frequency of severe and serious adverse reactions in patients ≥ 75 years was observed. Safety data of pembrolizumab in the adjuvant melanoma setting in patients ≥ 75 years are limited.

For subjects with relapsed or refractory classical Hodgkin lymphoma, clinical data for the use of pembrolizumab in patients ineligible to ASCT due to reasons other than failure to salvage chemotherapy are limited (see section 5.1).

After careful consideration of the potential increased risk, pembrolizumab may be used with appropriate medical management in these patients.

Patient Alert Card

All prescribers of KEYTRUDA must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of KEYTRUDA therapy with the patient. The patient will be provided with the Patient Alert Card with each prescription.

4.5 Interaction with other medicinal products and other forms of interaction

No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Since pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.

The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used after starting pembrolizumab to treat immune-related adverse reactions (see section 4.4).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab.

Pregnancy

There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 signaling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss (see section 5.3). These results indicate a potential risk, based on its mechanism of action, that administration of pembrolizumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth. Human immunoglobulins G4 (IgG4) are known to cross the placental barrier; therefore, being an IgG4, pembrolizumab has the potential to be transmitted from the mother to the developing foetus. Pembrolizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab.

Breast-feeding

It is unknown whether pembrolizumab is secreted in human milk. Since it is known that antibodies can be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision should be made whether to discontinue breast-feeding or to discontinue pembrolizumab, taking into account the benefit of breast-feeding for the child and the benefit of pembrolizumab therapy for the woman.

Fertility

No clinical data are available on the possible effects of pembrolizumab on fertility. There were no notable effects in the male and female reproductive organs in monkeys based on 1-month and 6-month repeat dose toxicity studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Pembrolizumab may have a minor influence on the ability to drive and use machines. Fatigue has been reported following administration of pembrolizumab (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of pembrolizumab (see “Description of selected adverse reactions” below).

The safety of pembrolizumab as monotherapy has been evaluated in 4,948 patients with advanced melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, or HNSCC across four doses (2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks) in clinical studies. The frequencies included below and in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the median observation time was 7.3 months (range: 1 day to 31 months) and the most frequent adverse reactions with pembrolizumab were fatigue (34.1%), rash (22.7%), nausea (21.7%), diarrhoea (21.5%), and pruritus (20.2%). The majority of adverse reactions reported for monotherapy were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions (see section 4.4).

The safety of pembrolizumab in combination with chemotherapy has been evaluated in 791 patients with NSCLC receiving 200 mg, 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks, in clinical studies. The frequencies included below and in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the most frequent adverse reactions were nausea (49%), anaemia (48%), fatigue (38%), constipation (34%), diarrhoea (31%), neutropaenia (29%), and decreased appetite (28%). Incidences of Grade 3-5 adverse reactions were 67% for pembrolizumab combination therapy and 66% for chemotherapy alone.

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination with chemotherapy or reported from post-marketing use of pembrolizumab are listed in Table 2. Adverse reactions known to occur with pembrolizumab or chemotherapies given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

*Adverse reaction frequencies presented in Table 2 may not be fully attributable to pembrolizumab alone but may contain contributions from the underlying disease or from other medicinal products used in a combination.

The following terms represent a group of related events that describe a medical condition rather than a single event.

Data for the following immune-related adverse reactions are based on patients who received pembrolizumab across four doses (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks, or 200 mg every 3 weeks) in clinical studies (see section 5.1). The management guidelines for these adverse reactions are described in section 4.4.

Immune-related adverse reactions (see section 4.4)

Immune-related pneumonitis

Pneumonitis occurred in 182 (3.7%) patients, including Grade 2, 3, 4 or 5 cases in 78 (1.6%), 48 (1.0%), 9 (0.2%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.7 months (range 2 days to 21.3 months). The median duration was 1.9 months (range 1 day to 17.2+ months). Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation (3.3%). Pneumonitis led to discontinuation of pembrolizumab in 75 (1.5%) patients. Pneumonitis resolved in 101 patients, 2 with sequelae.

In patients with NSCLC, pneumonitis occurred in 107 (4.9%), including Grade 2, 3, 4 or 5 cases in 39 (1.8%), 30 (1.4%), 10 (0.5%) and 9 (0.4%), respectively. In patients with NSCLC, pneumonitis occurred in 8.1% with a history of prior thoracic radiation.

Immune-related colitis

Colitis occurred in 97 (2.0%) patients, including Grade 2, 3 or 4 cases in 28 (0.6%), 56 (1.1%) and 3 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 3.8 months (range 7 days to 20.2 months). The median duration was 1.2 months (range 1 day to 8.7+ months). Colitis led to discontinuation of pembrolizumab in 28 (0.6%) patients. Colitis resolved in 75 patients, 1 with sequelae.

Immune-related hepatitis

Hepatitis occurred in 39 (0.8%) patients, including Grade 2, 3 or 4 cases in 7 (0.1%), 26 (0.5%) and 4 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 2.8 months (range 8 days to 21.4 months). The median duration was 1.1 months (range 1 day to 20.9+ months). Hepatitis led to discontinuation of pembrolizumab in 14 (0.3%) patients. Hepatitis resolved in 27 patients.

Immune-related nephritis

Nephritis occurred in 17 (0.3%) patients, including Grade 2, 3 or 4 cases in 3 (0.1%), 12 (0.2%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 5.1 months (range 12 days to 12.8 months). The median duration was 1.8 months (range 6 days to 10.5+ months). Nephritis led to discontinuation of pembrolizumab in 7 (0.1%) patients. Nephritis resolved in 9 patients, 1 with sequelae. In patients with non-squamous NSCLC treated with pembrolizumab in combination with pemetrexed and platinum chemotherapy (n=488), the incidence of nephritis was 1.4% (all Grades) with 0.8% Grade 3 and 0.4% Grade 4.

Immune-related endocrinopathies

Hypophysitis occurred in 32 (0.6%) patients, including Grade 2, 3 or 4 cases in 13 (0.3%), 15 (0.3%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypophysitis was 5.3 months (range 1 day to 17.7 months). The median duration was 1.7 months (range 3 days to 18.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 8 (0.2%) patients. Hypophysitis resolved in 9 patients, 7 with sequelae.

Hyperthyroidism occurred in 197 (4.0%) patients, including Grade 2 or 3 cases in 52 (1.1%) and 5 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 21.9 months). The median duration was 1.7 months (range 4 days to 15.5+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 3 (0.1%) patients. Hyperthyroidism resolved in 152 (77.2%) patients, 1 with sequelae.

Hypothyroidism occurred in 514 (10.4%) patients, including Grade 2 or 3 cases in 377 (7.6%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.5 months (range 1 day to 18.9 months). The median duration was not reached (range 2 days to 29.9+ months). Two patients (< 0.1%) discontinued pembrolizumab due to hypothyroidism. Hypothyroidism resolved in 107 (20.8%) patients, 9 with sequelae. In patients with cHL (n=241) the incidence of hypothyroidism was 14.1% (all Grades) with 0.4% Grade 3. In patients with HNSCC (n=609), the incidence of hypothyroidism was 15.1% (all Grades) with 0.5% Grade 3.

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed (see sections 4.2 and 4.4).

Complications of allogeneic HSCT in classical Hodgkin lymphoma

Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with pembrolizumab, 6 patients (26%) developed GVHD, one of which was fatal, and 2 patients (9%) developed severe hepatic VOD after reduced-intensity conditioning, one of which was fatal. The 23 patients had a median follow-up from subsequent allogeneic HSCT of 5.1 months (range: 0-26.2 months).

In patients treated with pembrolizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 23.8% for neutrophils decreased, 20.2% for lymphocytes decreased, 16.2% for haemoglobin decreased, 14.6% for leucocytes decreased, 10.3% for platelets decreased, 7.9% for glucose increased, 7.8% for phosphate decreased, 7.4% for sodium decreased, 4.6% for potassium decreased, 3.7% for ALT increased, 3.6% for creatinine increased, 3.5% for AST increased, 2.9% for calcium decreased, 2.6% for potassium increased, 2.5% for albumin decreased, 1.7% for calcium increased, 1.2% for alkaline phosphatase increased, 0.9% for glucose decreased, 0.7% for bilirubin increased, and 0.1% for sodium increased.

Immunogenicity

In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg every two or three weeks as monotherapy, 36 (1.8%) of 2,034 evaluable patients tested positive for treatment-emergent antibodies to pembrolizumab, of which 9 (0.4%) patients had neutralising antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody development.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no information on overdose with pembrolizumab.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.

KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. KEYTRUDA potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment.

Clinical efficacy and safety

Dosing for patients with melanoma and NSCLC

Pembrolizumab doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks were evaluated in melanoma or previously treated NSCLC clinical trials. Based on the dose/exposure relationships for efficacy and safety for pembrolizumab, there are no clinically significant differences in efficacy and safety between the doses of 200 mg or 2 mg/kg every 3 weeks in patients with melanoma or NSCLC. The recommended dose of pembrolizumab is 200 mg every 3 weeks.

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-006, a multicentre, controlled, Phase III study for the treatment of advanced melanoma in patients who were naïve to ipilimumab. Patients were randomised (1:1:1) to receive pembrolizumab 10 mg/kg every 2 (n=279) or 3 weeks (n=277) or ipilimumab 3 mg/kg every 3 weeks (n=278). Patients with BRAF V600E mutant melanoma were not required to have received prior BRAF inhibitor therapy.

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Assessment of tumour status was performed at 12 weeks, then every 6 weeks through week 48, followed by every 12 weeks thereafter.

Of the 834 patients, 60% were male, 44% were ≥ 65 years (median age was 62 years [range 18-89]) and 98% were white. Sixty-five percent of patients had M1c stage, 9% had a history of brain metastases, 66% had no and 34% had one prior therapy. Thirty-one percent had an ECOG Performance Status of 1, 69% had ECOG Performance Status of 0 and 32% had elevated LDH. BRAF mutations were reported in 302 (36%) patients. Among patients with BRAF mutant tumours, 139 (46%) were previously treated with a BRAF inhibitor.

The primary efficacy outcome measures were progression free survival (PFS; as assessed by Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1) and overall survival (OS). Secondary efficacy outcome measures were overall response rate (ORR) and response duration. Table 3 summarises key efficacy measures in patients naïve to treatment with ipilimumab at the final analysis performed after a minimum of 21 months of follow-up. Kaplan-Meier curves for OS and PFS based on the final analysis are shown in Figures 1 and 2.

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-002, a multicentre, controlled study for the treatment of advanced melanoma in patients previously treated with ipilimumab and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor. Patients were randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=180) or 10 mg/kg (n=181) every 3 weeks or chemotherapy (n=179; including dacarbazine, temozolomide, carboplatin, paclitaxel, or carboplatin+paclitaxel). The study excluded patients with autoimmune disease or those receiving immunosuppression; further exclusion criteria were a history of severe or life-threatening immune-related adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; ongoing adverse reactions ≥ Grade 2 from previous treatment with ipilimumab; previous severe hypersensitivity to other monoclonal antibodies; a history of pneumonitis or interstitial lung disease; HIV, hepatitis B or hepatitis C infection and ECOG Performance Status ≥ 2.

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Assessment of tumour status was performed at 12 weeks, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced independently verified progression of disease after the first scheduled disease assessment were able to crossover and receive 2 mg/kg or 10 mg/kg of pembrolizumab every 3 weeks in a double blind fashion.

Of the 540 patients, 61% were male, 43% were ≥ 65 years (median age was 62 years [range 15-89]) and 98% were white. Eighty-two percent had M1c stage, 73% had at least two and 32% of patients had three or more prior systemic therapies for advanced melanoma. Forty-five percent had an ECOG Performance Status of 1, 40% had elevated LDH and 23% had a BRAF mutated tumour.

The primary efficacy outcome measures were PFS as assessed by IRO using RECIST version 1.1 and OS. Secondary efficacy outcome measures were ORR and response duration. Table 4 summarises key efficacy measures at the final analysis in patients previously treated with ipilimumab, and the Kaplan-Meier curve for PFS is shown in Figure 3. Both pembrolizumab arms were superior to chemotherapy for PFS, and there was no difference between pembrolizumab doses. There was no statistically significant difference between pembrolizumab and chemotherapy in the final OS analysis that was not adjusted for the potentially confounding effects of crossover. Of the patients randomised to the chemotherapy arm, 55% crossed over and subsequently received treatment with pembrolizumab.

KEYNOTE-001: Open label study in melanoma patients naïve and previously treated with ipilimumab

The safety and efficacy of pembrolizumab for patients with advanced melanoma were investigated in an uncontrolled, open-label study, KEYNOTE-001. Efficacy was evaluated for 276 patients from two defined cohorts, one which included patients previously treated with ipilimumab (and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor) and the other which included patients naïve to treatment with ipilimumab. Patients were randomly assigned to receive pembrolizumab at a dose of 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Exclusion criteria were similar to those of KEYNOTE-002.

Of the 89 patients receiving 2 mg/kg of pembrolizumab who were previously treated with ipilimumab, 53% were male, 33% were ≥ 65 years of age and the median age was 59 years (range 18-88). All but two patients were white. Eighty-four percent had M1c stage and 8% of patients had a history of brain metastases. Seventy percent had at least two and 35% of patients had three or more prior systemic therapies for advanced melanoma. BRAF mutations were reported in 13% of the study population. All patients with BRAF mutant tumours were previously treated with a BRAF inhibitor.

Of the 51 patients receiving 2 mg/kg of pembrolizumab who were naïve to treatment with ipilimumab, 63% were male, 35% were ≥ 65 years of age and the median age was 60 years (range 35-80). All but one patient was white. Sixty-three percent had M1c stage and 2% of patients had a history of brain metastases. Forty-five percent had no prior therapies for advanced melanoma. BRAF mutations were reported in 20 (39%) patients. Among patients with BRAF mutant tumours, 10 (50%) were previously treated with a BRAF inhibitor.

The primary efficacy outcome measure was ORR as assessed by independent review using RECIST 1.1. Secondary efficacy outcome measures were disease control rate (DCR; including complete response, partial response and stable disease), response duration, PFS and OS. Tumour response was assessed at 12-week intervals. Table 5 summarises key efficacy measures in patients previously treated or naïve to treatment with ipilimumab, receiving pembrolizumab at a dose of 2 mg/kg based on a minimum follow-up time of 30 months for all patients.

§
Based on patients with a confirmed response by independent review, starting from the date the response was first recorded; n=23 for patients previously treated with ipilimumab; n=18 for patients naïve to treatment with ipilimumab

¶ Based on Kaplan-Meier estimation

Results for patients previously treated with ipilimumab (n=84) and naïve to treatment with ipilimumab (n=52) who received 10 mg/kg of pembrolizumab every 3 weeks were similar to those seen in patients who received 2 mg/kg of pembrolizumab every 3 weeks.

Sub-population analyses

BRAF mutation status in melanoma

A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who were BRAF wild type (n=414; 77%) or BRAF mutant with prior BRAF treatment (n=126; 23%) as summarised in Table 6.

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were BRAF wild type (n=525; 63%), BRAF mutant without prior BRAF treatment (n=163; 20%) and BRAF mutant with prior BRAF treatment (n=139; 17%) as summarised in Table 7.

A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who were PD-L1 positive (PD-L1 expression in ≥ 1% of tumour and tumour-associated immune cells relative to all viable tumour cells – MEL score) vs. PD-L1 negative. PD-L1 expression was tested retrospectively by immunohistochemistry assay with the 22C3 anti-PD-L1 antibody. Among patients who were evaluable for PD-L1 expression (79%), 69% (n=294) were PD-L1 positive and 31% (n=134) were PD-L1 negative. Table 8 summarises efficacy results by PD-L1 expression.

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were PD-L1 positive (n=671; 80%) vs. PD-L1 negative (n=150; 18%). Among patients who were evaluable for PD-L1 expression (98%), 82% were PD-L1 positive and 18% were PD-L1 negative. Table 9 summarizes efficacy results by PD-L1 expression.

In 20 subjects with ocular melanoma included in KEYNOTE-001, no objective responses were reported; stable disease was reported in 6 patients.

KEYNOTE-054: Placebo-controlled trial for the adjuvant treatment of patients with completely resected melanoma

The efficacy of pembrolizumab was evaluated in KEYNOTE-054, a multicentre, randomized, double-blind, placebo-controlled trial in patients with completely resected stage IIIA (> 1 mm lymph node metastasis), IIIB or IIIC melanoma. A total of 1,019 adult patients were randomized (1:1) to receive pembrolizumab 200 mg every three weeks (n=514) or placebo (n=505), for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer (AJCC) 7th edition stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥ 4 positive lymph nodes) and geographic region (North America, European countries, Australia and other countries as designated). Patients must have undergone lymph node dissection, and if indicated, radiotherapy within 13 weeks prior to starting treatment. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Patients who received prior therapy for melanoma other than surgery or interferon for thick primary melanomas without evidence of lymph node involvement were ineligible. Patients underwent imaging every 12 weeks after the first dose of pembrolizumab for the first two years, then every 6 months from year 3 to 5, and then annually.

Among the 1,019 patients, the baseline characteristics were: median age of 54 years (25% age 65 or older); 62% male; and ECOG PS of 0 (94%) and 1 (6%). Sixteen percent had stage IIIA; 46% had stage IIIB; 18% had stage IIIC (1-3 positive lymph nodes) and 20% had stage IIIC (≥ 4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type. PD-L1 expression was tested retrospectively by immunohistochemistry assay with the 22C3 anti-PD-L1 antibody; 84% of patients had PD-L1-positive melanoma (PD-L1 expression in ≥ 1% of tumour and tumour-associated immune cells relative to all viable tumour cells). The same scoring system was used for metastatic melanoma (MEL score).

The primary efficacy outcome measures were investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumours, where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. The trial demonstrated a statistically significant improvement in RFS for patients randomized to the pembrolizumab arm compared with placebo at the pre-specified interim analysis. Efficacy results based on an additional seven months of follow-up are summarized in Table 10 and Figure 4.

Table 10: Efficacy results in KEYNOTE-054

Endpoint

KEYTRUDA

200 mg every 3 weeks

n=514

Placebo

n=505

Number (%) of patients with event

158 (31%)

246 (49%)

Median in months (95% CI)

NR

21.7 (17.1, NR)

Hazard ratio* (98% CI)

0.56 (0.44, 0.72)

p-Value (stratified log-rank)

< 0.0001

RFS at 6 months

RFS rate

82%

73%

RFS at 12 months

RFS rate

76%

61%

RFS at 18 months

RFS rate

72%

54%

* Based on the stratified Cox proportional hazard model

NR = not reached

KEYNOTE-054 enrolled patients per AJCC 7th edition and a subgroup analysis of RFS per AJCC 8th edition was performed after the RFS study results were reported. A statistically significant improvement in RFS for patients randomized to the pembrolizumab arm compared with placebo was demonstrated in the overall population across resected stage III melanoma per AJCC 7th edition. Stage IIIA melanoma according to the AJCC 8th edition identifies a patient population with a better prognosis compared to stage IIIA according to AJCC 7th edition. Per the AJCC 8th edition classification, a total of 82 subjects were classified as stage IIIA; 42 in the pembrolizumab arm and 40 in the placebo arm; with a total of 13 RFS events; 6 in the pembrolizumab arm and 7 in the placebo arm. There is limited data on subjects with stage IIIA according to AJCC 8th edition at the time of this RFS analysis.

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-024, a multicentre, controlled study for the treatment of previously untreated metastatic NSCLC. Patients had PD-L1 expression with a ≥ 50% tumour proportion score (TPS) based on the PD-L1 IHC 22C3 pharmDxTM Kit. Patients were randomised (1:1) to receive pembrolizumab at a dose of 200 mg every 3 weeks (n=154) or investigator's choice platinum-containing chemotherapy (n=151; including pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin. Non-squamous patients could receive pemetrexed maintenance). Patients were treated with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with EGFR or ALK genomic tumour aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks. Patients on chemotherapy who experienced independently-verified progression of disease were able to crossover and receive pembrolizumab.

The primary efficacy outcome measure was PFS as assessed by BICR using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by BICR using RECIST 1.1). Table 12 summarizes key efficacy measures for the entire intent to treat (ITT) population. PFS and ORR results are reported from an interim analysis at a median follow-up of 11 months. OS results are reported from the final analysis at a median follow-up of 25 months.

In a subgroup analysis, a reduced survival benefit of pembrolizumab compared to chemotherapy was observed in the small number of patients who were never-smokers; however, due to the small number of patients, no definitive conclusions can be drawn from these data.

The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy was investigated in a multicentre, randomized, active-controlled, double-blind trial, KEYNOTE-189. Key eligibility criteria were metastatic non-squamous NSCLC, no prior systemic treatment for metastatic NSCLC, and no EGFR or ALK genomic tumour aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients were randomized (2:1) to receive one of the following regimens:

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of pembrolizumab was permitted beyond RECIST-defined disease progression by BICR or beyond discontinuation of pemetrexed if the patient was clinically stable and deriving clinical benefit as determined by the investigator. For patients who completed 24 months of therapy or had a complete response, treatment with pembrolizumab could be reinitiated for disease progression and administered for up to 1 additional year. Assessment of tumour status was performed at Week 6 and Week 12, followed by every 9 weeks thereafter. Patients receiving placebo plus chemotherapy who experienced independently-verified progression of disease were offered pembrolizumab as monotherapy.

Among the 616 patients in KEYNOTE-189, baseline characteristics were: median age of 64 years (49% age 65 or older); 59% male; 94% White and 3% Asian; 43% and 56% ECOG performance status of 0 or 1 respectively; 31% PD-L1 negative (TPS < 1%); and 18% with treated or untreated brain metastases at baseline. A total of 67 patients in the placebo plus chemotherapy arm crossed over to receive monotherapy pembrolizumab at the time of disease progression and 18 additional patients received a checkpoint inhibitor as subsequent therapy.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using RECIST 1.1. The median follow-up time was 10.5 months (range: 0.2 to 20.4 months). Table 13 summarises key efficacy measures. The Kaplan-Meier curves for OS and PFS are shown in Figures 7 and 8.

Table 13: Efficacy results in KEYNOTE-189

Endpoint

Pembrolizumab + Pemetrexed + Platinum Chemotherapy

n=410

Placebo + Pemetrexed + Platinum Chemotherapy

n=206

OS

Number (%) of patients with event

127 (31%)

108 (52%)

Hazard ratio* (95% CI)

0.49 (0.38, 0.64)

p-Value†

< 0.00001

Median in months (95% CI)

Not reached

(NA, NA)

11.3

(8.7, 15.1)

PFS

Number (%) of patients with event

244 (60%)

166 (81%)

Hazard ratio* (95% CI)

0.52 (0.43, 0.64)

p-Value†

< 0.00001

Median in months (95% CI)

8.8 (7.6, 9.2)

4.9 (4.7, 5.5)

Objective Response Rate

ORR‡ % (95% CI)

48% (43, 53)

19% (14, 25)

Complete response %

0.5%

0.5%

Partial response %

47%

18%

p-Value§

< 0.0001

Response duration

Median in months (range)

11.2

(1.1+, 18.0+)

7.8

(2.1+, 16.4+)

% with duration ≥ 6 months¶

81%

63%

% with duration ≥ 9 months¶

60%

44%

* Based on the stratified Cox proportional hazard model

†
Based on stratified log-rank test

‡
Based on patients with a best overall response as confirmed complete or partial response

§
Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status

A total of 57 NSCLC patients aged ≥ 75 years were enrolled in study KEYNOTE-189 (35 in the pembrolizumab combination and 22 in the control). A HR=2.09 [95% CI 0.84,5.23] in OS and HR=1.73 [95% CI 0.77,3.90] in PFS for pembrolizumab combination vs chemotherapy was reported within this study subgroup. Data about efficacy and safety of pembrolizumab in combination with platinum chemotherapy are limited in this patient population.

The efficacy of pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel was investigated in Study KEYNOTE-407, a randomised, double-blind, multicentre, placebo-controlled study. The key eligibility criteria for this study were metastatic squamous NSCLC, regardless of tumour PD-L1 expression status, and no prior systemic treatment for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomisation was stratified by tumour PD-L1 expression (TPS < 1% [negative] vs. TPS ≥ 1%), investigator's choice of paclitaxel or nab-paclitaxel, and geographic region (East Asia vs. non-East Asia). Patients were randomised (1:1) to one of the following treatment arms via intravenous infusion:

• Pembrolizumab 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by pembrolizumab 200 mg every 3 weeks. Pembrolizumab was administered prior to chemotherapy on Day 1.

• Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks.

Treatment with pembrolizumab or placebo continued until RECIST 1.1-defined progression of disease as determined by blinded independent central review (BICR), unacceptable toxicity, or a maximum of 24 months. Administration of pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.

Patients in the placebo arm were offered pembrolizumab as a single agent at the time of disease progression.

Assessment of tumour status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter.

A total of 559 patients were randomised. The study population characteristics were: median age of 65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; ECOG performance status of 0 (29%) and 1 (71%); and 8% with treated brain metastases at baseline. Thirty-five percent had tumour PD-L1 expression TPS < 1% [negative]; 19% were East Asian; and 60% received paclitaxel.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using RECIST 1.1. The median follow-up time was 7.8 months (range: 0.1 to 19.1 months). Table 15 summarises key efficacy measures. The Kaplan-Meier curves for OS and PFS are shown in Figures 9 and 10.

A total of 65 NSCLC patients aged ≥ 75 years were enrolled in study KEYNOTE-407 (34 in the pembrolizumab combination and 31 in the control). An HR=0.96 [95% CI 0.37,2.52] in OS, an HR=0.60 [95% CI 0.29,1.21] in PFS, and an ORR of 47% and 42% for pembrolizumab combination vs chemotherapy was reported within this study subgroup. Data about efficacy and safety of pembrolizumab in combination with platinum chemotherapy are limited in this patient population.

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-010, a multicentre, open-label, controlled study for the treatment of advanced NSCLC in patients previously treated with platinum-containing chemotherapy. Patients had PD-L1 expression with a ≥ 1% TPS based on the PD-L1 IHC 22C3 pharmDxTM Kit. Patients with EGFR activation mutation or ALK translocation also had disease progression on approved therapy for these mutations prior to receiving pembrolizumab. Patients were randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=344) or 10 mg/kg (n=346) every 3 weeks or docetaxel at a dose of 75 mg/m2 every 3 weeks (n=343) until disease progression or unacceptable toxicity. The trial excluded patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks.

The baseline characteristics for this population included: median age 63 years (42% age 65 or older); 61% male; 72% White and 21% Asian and 34% and 66% with an ECOG performance status 0 and 1, respectively. Disease characteristics were squamous (21%) and non-squamous (70%); M1 (91%); stable brain metastases (15%) and the incidence of mutations was EGFR (8%) or ALK (1%). Prior therapy included platinum-doublet regimen (100%); patients received one (69%) or two or more (29%) treatment lines.

The primary efficacy outcome measures were OS and PFS as assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary efficacy outcome measures were ORR and response duration. Table 17 summarises key efficacy measures for the entire population (TPS ≥ 1%) and for the patients with TPS ≥ 50% and the Kaplan-Meier curve for OS (TPS ≥ 1%) is shown in Figure 11.

Table 17: Response to pembrolizumab 2 or 10 mg/kg every 3 weeks in previously treated patients with NSCLC in KEYNOTE-010

Efficacy results were similar for the 2 mg/kg and 10 mg/kg pembrolizumab arms. Efficacy results for OS were consistent regardless of the age of tumour specimen (new vs. archival) based on an intergroup comparison.

In subgroup analyses, a reduced survival benefit of pembrolizumab compared to docetaxel was observed for patients who were never-smokers or patients with tumours harbouring EGFR activating mutations who received at least platinum-based chemotherapy and a tyrosine kinase inhibitor; however, due to the small numbers of patients, no definitive conclusions can be drawn from these data.

The efficacy and safety of pembrolizumab in patients with tumours that do not express PD-L1 have not been established.

The efficacy of pembrolizumab was investigated in KEYNOTE-087 and KEYNOTE-013, two multicentre, open-label studies for the treatment of 241 patients with cHL. These studies enrolled patients who failed ASCT and BV, who were ineligible for ASCT because they were unable to achieve a complete or partial remission to salvage chemotherapy and failed BV, or who failed ASCT and did not receive BV. Five study subjects were ineligible to ASCT due to reasons other than failure to salvage chemotherapy. Both studies included patients regardless of PD-L1 expression. Patients with active, non-infectious pneumonitis, an allogeneic transplant within the past 5 years (or > 5 years but with GVHD), active autoimmune disease or a medical condition that required immunosuppression were ineligible for either trial. Patients received pembrolizumab 200 mg every 3 weeks (n=210; KEYNOTE-087) or 10 mg/kg every 2 weeks (n=31; KEYNOTE-013) until unacceptable toxicity or documented disease progression.

Among KEYNOTE-087 patients, the baseline characteristics were median age 35 years (9% age 65 or older); 54% male; 88% White; and 49% and 51% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range 1 to 12). Eighty-one percent were refractory to at least one prior therapy, including 35% who were refractory to first line therapy. Sixty-one percent of patients had received Auto-SCT, 38% were transplant ineligible; 17% had no prior brentuximab vedotin use; and 36% of patients had prior radiation therapy. Disease subtypes were 80% nodular sclerosis, 11% mixed cellularity, 4% lymphocyte-rich and 2% lymphocyte-depleted.

Among KEYNOTE-013 patients, the baseline characteristics were median age 32 years (7% age 65 or older), 58% male, 94% White; and 45% and 55% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 5 (range 2 to 15). Eighty-seven percent were refractory to at least one prior therapy, including 39% who were refractory to first line therapy. Seventy-four percent of patients had received Auto-SCT, 26% were transplant ineligible, and 42% of patients had prior radiation therapy. Disease subtypes were 97% nodular sclerosis and 3% mixed cellularity.

The major efficacy outcome measures (ORR and CRR) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria. Secondary efficacy outcome measures were duration of response, PFS and OS. Response was assessed in KN087 and KN013 every 12 and 8 weeks, respectively, with the first planned post-baseline assessment at week 12. Efficacy results are summarized in Table 18.

Table 18: Efficacy results in KEYNOTE-087 and KEYNOTE-013

KEYNOTE-087a

KEYNOTE-013b

Endpoint

Pembrolizumab

200 mg every 3 weeks

n=210

Pembrolizumab

10 mg/kg every 2 weeks

n=31

Objective response ratec

ORR % (95% CI)

69% (62.3, 75.2)

58% (39.1, 75.5)

Complete Remission

22%

19%

Partial Remission

47%

39%

Response durationc

Median in months (range)

11.1 (0.0+, 11.1)d

Not reached (0.0+, 26.1+)e

% with duration ≥ 6-months

76%f

80%g

% with duration ≥ 12-months

---

70%h

Time to response

Median in months (range)

2.8 (2.1, 8.8)d

2.8 (2.4, 8.6)e

PFSc

Number (%) of patients with event

70 (33%)

18 (58%)

Median in months (95% CI)

11.3 (10.8, Not reached)

11.4 (4.9, 27.8)

6-month PFS rate

72%

66%

9-month PFS rate

62%

---

12-month PFS rate

---

48%

OS

Number (%) of patients with event

4 (2%)

4 (13%)

6-month OS rate

99.5%

100%

12-month OS rate

97.6%

87.1%

a Median follow-up time of 10.1 months

b Median follow-up time of 28.7 months

c Assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria by PET CT scans

d Based on patients (n=145) with a response by independent review

e Based on patients (n=18) with a response by independent review

f Based on Kaplan-Meier estimation; includes 31 patients with responses of 6 months or longer

g Based on Kaplan-Meier estimation; includes 9 patients with responses of 6 months or longer

h Based on Kaplan-Meier estimation; includes 7 patients with responses of 12 months or longer

Safety and efficacy in elderly patients

Overall, 20 cHL patients ≥ 65 years were treated with pembrolizumab in studies KEYNOTE-087 and KEYNOTE-013. Data from these patients are too limited to draw any conclusion on safety or efficacy in this population.

Urothelial Carcinoma

KEYNOTE-045: Controlled trial in urothelial carcinoma patients who have received prior platinum-containing chemotherapy

The safety and efficacy of pembrolizumab were evaluated in KEYNOTE-045, a multicentre, randomised (1:1), controlled study for the treatment of locally advanced or metastatic urothelial carcinoma in patients with disease progression on or after platinum-containing chemotherapy. Patients must have received first line platinum-containing regimen for locally advanced/metastatic disease or as neoadjuvant/adjuvant treatment, with recurrence/progression ≤ 12 months following completion of therapy. Patients were randomised (1:1) to receive either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator's choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=84), docetaxel 75 mg/m2 (n=84), or vinflunine 320 mg/m2 (n=87). Patients were treated with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with autoimmune disease, a medical condition that required immunosuppression and patients with more than 2 prior lines of systemic chemotherapy for metastatic urothelial cancer. Patients with an ECOG performance status of 2 had to have a hemoglobin ≥ 10 g/dL, could not have liver metastases, and must have received the last dose of their last prior chemotherapy regimen ≥ 3 months prior to enrollment. Assessment of tumour status was performed at 9 weeks after the first dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter.

Among the 542 randomised patients in KEYNOTE-045, baseline characteristics were: median age 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 56% ECOG performance status of 1 and 1% ECOG performance status of 2; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumour in the lower tract and 14% had a primary tumour in the upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% was treated with other platinum-based regimens.

The primary efficacy outcomes were OS and PFS as assessed by BICR using RECIST v1.1. Secondary outcome measures were ORR (as assessed by BICR using RECIST v1.1) and duration of response. Table 19 summarises the key efficacy measures for the ITT population at the final analysis. The Kaplan-Meier curve based on the final analysis for OS is shown in Figure 12. The study demonstrated statistically significant improvements in OS and ORR for patients randomised to pembrolizumab as compared to chemotherapy. There was no statistically significant difference between pembrolizumab and chemotherapy with respect to PFS.

Patient-reported outcomes (PROs) were assessed using EORTC QLQ-C30. A prolonged time to deterioration in EORTC QLQ-C30 global health status/QoL was observed for patients treated with pembrolizumab compared to investigator's choice chemotherapy (HR 0.70; 95% CI 0.55-0.90). Over 15 weeks of follow-up, patients treated with pembrolizumab had stable global health status/QoL, while those treated with investigator's choice chemotherapy had a decline in global health status/QoL. These results should be interpreted in the context of the open-label study design and therefore taken cautiously.

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-052, a multicentre, open-label study for the treatment of locally advanced or metastatic urothelial carcinoma in patients who were not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or disease progression. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with autoimmune disease or a medical condition that required immunosuppression. Assessment of tumour status was performed at 9 weeks after the first dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter.

Among 370 patients with urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy baseline characteristics were: median age 74 years (82% age 65 or older); 77% male; and 89% White and 7% Asian. Eighty-eight percent had M1 disease and 12% had M0 disease. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons for cisplatin ineligibility included: baseline creatinine clearance of < 60 mL/min (50%), ECOG performance status of 2 (32%), ECOG performance status of 2 and baseline creatinine clearance of < 60 mL/min (9%), and other (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss; 9%). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. Eighty-one percent had a primary tumour in the lower tract, and 19% of patients had a primary tumour in the upper tract.

The primary efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Secondary efficacy outcome measures were duration of response, PFS, and OS. Table 21 summarises the key efficacy measures for the study population based on a median follow-up time of 11.5 months for all patients.

‡
Based on Kaplan-Meier estimates; includes 85 patients with response of 6 months or longer

An analysis was performed in KEYNOTE-052 in patients who had PD-L1 CPS < 10 (n=251; 68%) or ≥ 10 (n=110; 30%) (see Table 22).

Table 22: ORR and OS by PD-L1 Expression

Endpoint

CPS < 10

N=251

CPS ≥ 10

N=110

Objective Response Rate*

ORR %, (95% CI)

21% (16, 26)

47% (38, 57)

OS

Median in months (95% CI)

10 (8, 12)

19 (12, Not reached)

12-month OS rate

42%

61%

* BICR using RECIST 1.1

KEYNOTE-361 is an ongoing Phase III, randomised, controlled, open-label clinical trial of pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy as first-line treatment in subjects with advanced or metastatic urothelial carcinoma. Preliminary data from an early review showed a reduced survival with pembrolizumab monotherapy in patients whose tumours express PD-L1 with a CPS < 10 compared with standard chemotherapy.

Based on a recommendation by an external Data Monitoring Committee, the accrual in the pembrolizumab monotherapy arm was stopped for patients whose tumours express PD-L1 with a CPS < 10. The pembrolizumab monotherapy arm remains open only to patients whose tumours express PD-L1 with a CPS ≥ 10. Subjects whose tumours express PD-L1 CPS < 10 already enrolled into the pembrolizumab monotherapy arm can continue treatment. Randomisation to the chemotherapy and the chemotherapy-pembrolizumab arms remains open.

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-040, a multicentre, open-label, randomised, controlled study for the treatment of recurrent or metastatic HNSCC in patients who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy, and were not amenable to local therapy with curative intent. Patients were stratified by PD-L1 expression (TPS ≥ 50%), HPV status and ECOG performance status and then randomised (1:1) to receive either pembrolizumab 200 mg every 3 weeks (n=247) or one of three standard treatments (n=248): methotrexate 40 mg/m2 once weekly (n=64), docetaxel 75 mg/m2 once every 3 weeks (n=99), or cetuximab 400 mg/m2 loading dose and then 250 mg/m2 once weekly (n=71). Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. The study excluded patients with active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or who were previously treated with 3 or more systemic regimens for recurrent and/or metastatic HNSCC. Assessment of tumour status was performed at 9 weeks, then every 6 weeks through week 52, followed by every 9 weeks through 24 months.

Among the 495 patients in KEYNOTE-040, 129 (26%) had tumours that expressed PD-L1 with a TPS ≥ 50% based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these 129 patients included: median age 62 years (40% age 65 or older); 81% male; 78% White, 11% Asian, and 2% Black; 23% and 77% with an ECOG performance status 0 or 1, respectively; and 19% with HPV positive tumours. Sixty-seven percent (67%) of patients had M1 disease and the majority had Stage IV disease (Stage IV 32%, Stage IVa 14%, Stage IVb 4%, and Stage IVc 44%). Sixteen percent (16%) had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy, and 84% had received 1-2 prior systemic regimens for metastatic disease.

The primary efficacy outcome was OS in the ITT population. The initial analysis resulted in a HR for OS of 0.82 (95% CI: 0.67, 1.01) with a one-sided p-value of 0.0316. The median OS was 8.4 months for pembrolizumab compared to 7.1 months for standard treatment. Table 23 summarises the key efficacy measures for the TPS ≥ 50% population. The Kaplan-Meier curve for OS for the TPS ≥ 50% population is shown in Figure 13.

Table 23: Efficacy of pembrolizumab 200 mg every 3 weeks in HNSCC patients with TPS ≥ 50% who were previously treated with platinum chemotherapy in KEYNOTE-040

The European Medicines Agency has deferred the obligation to submit the results of studies with pembrolizumab in one or more subsets of the paediatric population in treatment of all conditions included in the category of malignant neoplasms (except nervous system, haematopoietic and lymphoid tissue) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of pembrolizumab was studied in 2,993 patients with metastatic or unresectable melanoma, NSCLC, or carcinoma who received doses in the range of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks.

Absorption

Pembrolizumab is administered via the intravenous route and therefore is immediately and completely bioavailable.

Distribution

Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at steady state is small (~6.0 L; CV: 20%). As expected for an antibody, pembrolizumab does not bind to plasma proteins in a specific manner.

Biotransformation

Pembrolizumab is catabolised through non-specific pathways; metabolism does not contribute to its clearance.

Elimination

Pembrolizumab CL is approximately 23% lower (geometric mean, 195 mL/day [CV%: 40%]) after achieving maximal change at steady-state compared with the first dose (252 mL/day [CV%: 37%]); this decrease in CL with time is not considered clinically meaningful. The geometric mean value (CV%) for the terminal half-life is 22 days (32%) at steady-state.

Linearity/non-linearity

Exposure to pembrolizumab as expressed by peak concentration (Cmax) or area under the plasma concentration time curve (AUC) increased dose proportionally within the dose range for efficacy. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3 week regimen and the systemic accumulation was 2.1-fold. The median trough concentrations (Cmin) at steady-state were approximately 22 mcg/mL at a dose of 2 mg/kg every 3 weeks and 29 mcg/mL at a dose of 200 mg every 3 weeks. The median area under the concentration time curve at steady state over 3 weeks (AUC0-3weeks) was 794 mcg∙day/mL at a dose of 2 mg/kg every 3 weeks and 1,053 mcg∙day/mL at a dose of 200 mg every 3 weeks.

Following administration of pembrolizumab 200 mg every 3 weeks in patients with cHL, the observed median Cmin at steady-state was up to 40% higher than that in other tumour types treated with the same dosage; however, the range of trough concentrations is similar. There are no notable differences in median Cmax between cHL and other tumour types. Based on available safety data in cHL and other tumour types, these differences are not clinically meaningful.

Special populations

The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The following factors had no clinically important effect on the clearance of pembrolizumab: age (range 15-94 years), gender, race, mild or moderate renal impairment, mild hepatic impairment and tumour burden. The relationship between body weight and clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and similar control of exposure.

Renal impairment

The effect of renal impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Pembrolizumab has not been studied in patients with severe renal impairment.

Hepatic impairment

The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild hepatic impairment (as defined using the US National Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepatic function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic function. Pembrolizumab has not been studied in patients with moderate or severe hepatic impairment (see section 4.2).

5.3 Preclinical safety data

The safety of pembrolizumab was evaluated in a 1-month and a 6-month repeat-dose toxicity study in Cynomolgus monkeys administered intravenous doses of 6, 40 or 200 mg/kg once a week in the 1-month study and once every two weeks in the 6-month study, followed by a 4-month treatment-free period. No findings of toxicological significance were observed and the no observed adverse effect level (NOAEL) in both studies was ≥ 200 mg/kg, which produced exposure multiples of 19 and 94 times the exposure in humans at doses of 10 and 2 mg/kg, respectively. The exposure multiple between the NOAEL and a human dose of 200 mg was 74.

Animal reproduction studies have not been conducted with pembrolizumab. The PD-1/PD-L1 pathway is thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.

Animal fertility studies have not been conducted with pembrolizumab. In 1 month and 6 month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, many animals in these studies were not sexually mature.

6. Pharmaceutical particulars

6.1 List of excipients

L-histidine

L-histidine hydrochloride monohydrate

Sucrose

Polysorbate 80

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

2 years.

After preparation of infusion

From a microbiological point of view, the product, once diluted, should be used immediately. The diluted solution must not be frozen. If not used immediately, chemical and physical in-use stability of KEYTRUDA has been demonstrated for 24 hours at 2°C to 8°C. This 24 hour hold may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperature prior to use.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

• Prior to dilution, the vial of liquid can be out of refrigeration (temperatures at or below 25°C) for up to 24 hours.

• Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. The concentrate is a clear to slightly opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are observed.

• Withdraw the required volume up to 4 mL (100 mg) of concentrate and transfer into an intravenous bag containing sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Each vial contains an excess fill of 0.25 ml (total content per vial 4.25 ml) to ensure the recovery of 4 ml of concentrate. Mix diluted solution by gentle inversion.

• From a microbiological point of view, the product, once diluted, should be used immediately. The diluted solution must not be frozen. If not used immediately, chemical and physical in-use stability of KEYTRUDA has been demonstrated for 24 hours at 2°C to 8°C. This 24 hour hold may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperature prior to use. Administer the infusion solution intravenously over 30 minutes using a sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line or add-on filter.

• Do not co-administer other medicinal products through the same infusion line.

• KEYTRUDA is for single use only. Discard any unused portion left in the vial.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

The Netherlands

8. Marketing authorisation number(s)

EU/1/15/1024/002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 17 July 2015

10. Date of revision of the text

11 March 2019

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.